Autoimmune thyroid disease (AITD) affects at least 6 percent of all women in their lifetime, and more than 10 percent of older women. The broad aim of our research program is to understand the causes of human autoimmune thyroid disease, the mechanisms involved in controlling the immune response, and, if possible, to develop preventive or therapeutic measures based on the immunology of the disease. Genetic factors including inheritance of MHC genes and specific CTLA4 alleles have been shown by many investigators to play a role in predisposing to Graves' disease. Responses to specific TSH receptor (TSH-R), and thyroid peroxidase (TPO) epitopes, have been demonstrated for T cells, T cell lines, and T cell clones in patients with Graves' disease. We will study the mechanism through which HLA-DRbeta1*03 and DQalpha1*05 are associated with Graves' disease, by purifying these molecules and studying the affinity of TSH-R and TPO peptides for binding. We will ask whether the binding affinity corresponds with the ability of the epitopes to stimulate T cells. We will also determine whether specific subgroups of DRbeta1*03 are primarily associated with Graves' disease, and why the DRbeta1*03 molecule found in Black Americans is not associated with Graves' disease, while the molecule found in Caucasians is associated with Graves' disease. We will also analyze the relative binding affinity of TSH-R and TPO epitopes for DRbeta1*07 and DQalpha1*02, which appear to be protective factors and, in theory, might not bind the epitopes. We will assess the function of CTLA4 in patients and control subjects in relation to inheritance of a specific allele associated with development of Graves' disease. Expression of the gene will be studied by FACs analysis and resting in stimulated cells, and function will be studied by use of anti-CTLA4 antibodies during in vitro culture of lymphocytes with antigen and nonspecific T cell stimulating molecules. Secretion of IL-2 during proliferation with/without anti-CTLA4, and apoptosis after withdrawal of IL-2, will also be studied as markers for CTLA4 action. CTLA4 function will be evaluated in T cell subsets. The studies planned have direct bearing on development of AITD in humans, and also apply to other autoimmune disease such as Diabetes.